Polymeric implants are useful as delivery systems for the sustained and controlled release of bioactive agents to animals, including humans. The implants may be preformed as polymeric solids or as pharmaceutical liquids in mechanical reservoirs. These kinds of implants are inserted into a patient's body by invasive, surgical procedures. However, these surgical procedures are uncomfortable and can be dangerous. Also they require further surgical intervention to remove the implant or reservoir after the pharmaceutical delivery is complete. For these reasons, implant technology has long concentrated upon biodegradable implants. However, many biodegradable implants require the invasive, surgical procedure to achieve the implantation. Recently, injectable, biodegradable implants have been developed that avoid the need for such surgical procedures. One such implant system is based upon microparticles while another is based upon implant formation in situ by injection of a flowable composition. Such flowable compositions may be composed of polymers that are liquid at ambient temperature but solidify upon heating (pluronics), solutions of polymer that coagulate upon contact with body fluid, or solutions of polymer that remain liquid but are so viscous that they do not readily disperse when injected.
The polymers for such controlled release implants have been a focus of research for years. Their biodegradability, release control, burst effect, solidification and additional characteristics have been improved through such research. Pluronics, polyesters, polyamides, polyethers and hybrids thereof are a few examples of these polymers. By far, the most popular polymer for use in a biodegradable implant is the polyester.
The polyester and its close relatives, the polyanhydride and polycarbonate are well-known and have been used in pharmaceutical application for many years. For example, polyglycolide is the polymeric material typically used for absorbable sutures. The biocompatibility of these polyesters is due in part to the fact that they are degraded by routine biochemical pathways and result in naturally occurring metabolic products.
The biodegradability of these polymers is based upon their ability to be hydrolyzed. In living tissue, their degradation occurs through cleavage of the ester or ester-like bond. This ester cleavage is facilitated by nucleophilic groups, such as amine groups, within the enzymatic site of an appropriate enzyme, by nucleophilic groups of blood serum molecules, and by nucleophilic compounds usually in the presence of water. This facile biodegradability is a significant benefit for medical use but the susceptibility also presents a problem.
A wide variety of bioactive agents that are suitable for delivery via biodegradable implants contain such nucleophilic groups. These bioactive agents include natural and synthetic peptides, polypeptides, proteins, nucleotides, oligonucleotides, polynucleotides and organic small molecules that have pharmacological and physiological activity. It is readily recognized that these molecules often contain one or more nucleophilic groups such as amine groups.
The presence of a nucleophilic functional group on the bioactive agent can lead to an interaction between the agent and the biodegradable polymer of the composition. Consequently, whenever the agent and biodegradable polymer are combined, that same degradation activity can occur through interaction of the agent upon the biodegradable polymer rather than solely through the interaction of living tissue with the biodegradable polymer. Such an interaction can affect either the physical or chemical character of the composition resulting in a loss of the advantages of a sustained and controlled delivery implant. This deleterious interaction can affect the character and stability of the composition before administration, can affect the formation of a consistent implant upon administration, and can affect the controlled and sustained release of the bioactive agent from the implant.
Therefore, there is a need to develop controlled release compositions that will prevent or minimize undesirable degradation of the controlled release polymer by the bioactive agent. A further need is the development of implant precursors and/or injectable implant compositions that of form stable and consistent implants for the delivery of bioactive agents. There is also a need to develop a controlled release composition that can be formulated and stored as a unified mixture of composition polymer and bioactive agent. Further, there is a need to develop such a unified composition which will provide implants with variable duration of controlled release of the bioactive agent.